Scleroderma is a rare disease with a stable incidence of approximately 19 cases per 1 million persons. The cause of scleroderma is unknown. However, the genetic predisposition is important. Abnormalities involve autoimmunity and alteration of endothelial cell and fibroblast function. Indeed, systemic sclerosis is probably the most severe of the auto-immune diseases with 50% mortality within 5 years of diagnosis.
Scleroderma is a disease of the connective tissue characterized by fibrosis of the skin and internal organs, leading to organ failure and death. Scleroderma has a spectrum of manifestations and a variety of therapeutic implications. It comprises localized scleroderma, systemic sclerosis, scleroderma-like disorders, and sine scleroderma. Whilst localized scleroderma is a rare dermatologic disease associated with fibrosis and manifestations limited to skin, systemic sclerosis is a multi-system disease with variable risk for internal organ involvement and variation in the extent of skin disease. Systemic sclerosis can be diffuse or limited. Limited systemic sclerosis is also called CREST (calcinosis, Raynaud's esophageal dysfunction, sclerodactyly, telangiectasiae). Systemic sclerosis comprises: scleroderma lung disease, scleroderma renal crisis, cardiac manifestations, muscular weakness including fatigue or limited CREST, gastrointestinal dysmotility and spasm, and abnormalities in the central, peripheral and autonomic nervous system. With regard to the nervous system abnormalities, carpal tunnel syndrome followed by trigeminal neuralgia are the most common. Scleroderma-like disorders are believed to be related to industrial environment exposure. In sine disease, there is internal organ involvement without skin changes.
The major manifestations of scleroderma and in particular of systemic sclerosis are inappropriate excessive collagen synthesis and deposition, endothelial dysfunction, spasm, collapse and obliteration by fibrosis. In terms of diagnosis, an important clinical parameter is skin thickening proximal to the metacarpophalangeal joints. Raynaud's phenomenon is a frequent, almost universal component of scleroderma. It is diagnosed by color changes of the skin upon cold exposure. Ischemia and skin thickening are symptoms of Raynaud's disease.
Several underlying biological processes are implicated in the initiation, severity and progression of the disease and include vascular dysfunction, endothelial cell activation and damage, leukocyte accumulation, auto-antibody production and crucially, an uncontrolled fibrotic response which may lead to death. Fibroblasts have a pivotal role in the pathogenesis of this disease. Primary fibroblasts obtained from patients with scleroderma exhibit many of the characteristic properties of the disease seen in vivo, notably increased extracellular matrix synthesis and deposition, notably of collagen and fibronectin, and altered growth factor and cytokine production such as of TGFβ and CTGF (“Increased collagen synthesis by scleroderma skin fibroblasts in vitro” J. Clin. Invest. 54, p. 880-89 LeRoy (1974)).
There is no curative treatment of scleroderma. Innovative but high-risk therapy proposed autologous stem cell transplantation. In particular, there are currently no treatments for scleroderma targeting the fibrotic process.
Identification of the genes associated with disease risk and scleroderma progression may lead to the development of effective strategies for intervention at various stages of the disease.
Although there is presently no cure for scleroderma, several agents or treatments are presently being used to treat scleroderma symptoms. Such anti-scleroderma agents, which may be used as combination therapy according to the invention, are summarized e.g. by Leighton C. (Drugs 61(3) p. 419-27 (2001)) or Wigley and Sule (Expert opinion on Investigational Drugs 10(1) p. 3148 (2001)), which are fully incorporated by reference herein.
A recent publication of B. A. Hocevar et al. (The EMBO Journal Vol. 18 No. 5 p. 1345-56 (1999)) has suggested that TGF-β-mediated gene induction would involve activation of JNK, since JNK has been shown to modulate promoters containing both AP-1 (a transcription factor, formed from a heterodimer of the products of the proto-oncogenes fos and jun and CRE sites through its phosphorylation and activation of c-Jun and ATF-2 which is a c-Jun transcription factor participating in the transcriptional activation of c-Jun gene.
c-Jun is a protein that is forming homodimers and heterodimers (with e.g. c-Fos) to produce the transactivating complex AP-1 which is required for the activation of many genes (e.g. matrix metalloproteinases) involved in the inflammatory response. The JNKs (c-Jun N-terminal Kinases) were discovered when it was found that several different stimuli such as UV light and TNF-α stimulated phosphorylation of c-Jun on specific serine residues in the N-terminus of the protein. The JNKs are also involved in relaying stress-type extramolecular signals, the ERK (extracellular regulated kinases) pathway is primarily responsible for transducing mitogenic/differentiation signals to the cell nucleus.
JNK inhibitors are disclosed in various patent applications. For instance, EP 1110957 describing benzazole derivatives in particular for the treatment or prevention of disorders associated with the abnormal expression or activity of JNK2 and/or 3, including autoimmune diseases such as Multiple Sclerosis, rheumatoid arthritis or asthma.
Recently, Anania F. A. et al. (Free Radical Biol. Med., 30(8), p. 846-57 (2001)) mentioned that JNK activation appears to be critical in the signaling cascade of oxidative metabolites of chronic alcoholic related liver injury and collagen gene activation that leads to liver fibrosis before cirrhosis.
WO 9855110, Dalhousie University teaches the use of compounds such as 1-(5-oxohexyl)-3,7-dimethylxanthine (pentoxifylline) or functional derivatives thereof to reduce the effect of PDGF-induced c-Jun gene expression in order to cure fibrosis diseases in which PDGF (Platelet Derived Growth Factor) is involved and acts as a stimulant.
The use of other compounds such as [5-chloro-2(3H)benzoxazolone](chlorzoxazone) and oxazolamine as pharmacological activators of the intermediate-conductance Ca2+-activated K+ channel are described to be therapeutically beneficial in cystic fibrosis and vascular diseases (Am. J. Physiol., 278(3, Pt. 1), C570-C581 (English) 2000).